Summary Endothelial dysfunction is part of the causes of many micro and macrovascular diseases that can lead to serious morbidity and mortality. It is a result of complex interactions between vascular cells including endothelial cells, pericytes, smooth muscle cells and immune cells, and is characterized by hemodynamic changes, microcirculatory disturbances, and uncoupling between blood flow and metabolic requirements. The development of a variety of diseases, including hypertension, myocardial infarction, stroke, preeclampsia, pulmonary arterial hypertension, diabetic ulcer, and end-organ damages, can all be partly attributed to vascular dysfunction, and each of these diseases incurs billions in health cost each year in the US alone. Although better care has improved the survival of patients with endothelial dysfunction-associated diseases, the progression of endothelial dysfunction in a large population of patients cannot be prevented by existing drugs, perhaps due to the lack of therapeutics that can actively improve endothelial functions. Clearly, novel strategies that can actively improve vascular functions are much needed. Recent advances have shown that the signaling of a group of vascular receptors, CLR/RAMP receptors, and their ligands is essential for vascular development during embryogenesis and throughout adulthood. Consistently, the receptor ligands have been shown to improve angiogenesis, vasculogenesis and endothelial barrier functions, and prevent hemodynamic disturbances in animals. Importantly, we have recently discovered a group of long-acting superagonists that potently activate multiple CLR/RAMP receptors. Accordingly, we propose to develop a hormonal therapy based on these newly invented superagonists to improve blood flow and vascular compliance in patients with endothelial dysfunction-associated diseases. In this proof-of-concept study, we will evaluate further this series of compounds to optimize their pharmacokinetic and pharmacodynamic characteristics in vivo, and identify the most potent drug candidate in Aim 1. In Aim 2, we will investigate the efficacy and identify the most efficacious dose of the selected lead analog for the treatment of spontaneous hypertension and cardiac hypertrophy in rats. The proposed therapy represents a novel pharmacological approach to specifically target a group of vascular receptors, and to reduce the mortality and morbidity resulting from endothelial dysfunction-associated etiology. Successful completion of this Phase I SBIR proposal will provide us with critical information needed to select a novel drug candidate for further preclinical development.